Summary Amyloid-? (??), ?-synuclein (?-syn) and islet amyloid polypeptide (IAPP) self-assemble into amyloids associated with Alzheimer?s disease (AD), Parkinson?s disease (PD) and type 2 diabetes (T2D), respectively. The amyloid inhibition of a single amyloidogenic protein may not suffice as a therapeutic approach, as increasing evidence supports an amyloid formation molecular link between the three molecules in diseases. One of the proposed approaches to inhibit amyloid formation is through ?-wrapin dimeric proteins which bind, sequester, and thus inhibit amyloid formation and toxicity of the aforementioned amyloidogenic proteins. Two recently discovered ?- wrapin protein variants, AS10 and ZSYM73, may pave the way for future therapeutic approaches: (i) AS10 is a triple-targeting ?-wrapin variant with sub-micromolar affinity for all three amyloidogenic proteins, and (ii) ZSYM73 is a single-targeting ?-wrapin variant with pM affinity for ??. Evidently, the discovery of novel highly potent and highly specific single and multi-targeting ?-wrapins may pave the way for novel effective therapeutic agents. Despite the success of experimental methods in the discovery of new ?-wrapin variants with high affinity, phage- display methods (i) primarily rely on intuition on choosing the mutable positions for modifications, and (ii) cannot be introduced to optimize a ?-wrapin?s binding toward multiple receptors at a time. Thus, when aiming at increasing a ?-wrapin?s affinity for one or multiple amyloidogenic proteins, several mutants need to be tested experimentally, making the procedure inefficient, especially when multi-targeting properties are desired. We recently used computational methods to uncover the molecular binding and specificity determinants associated with particular ?-wrapins binding to A? and ?-syn. Here, we propose to use an analogous approach comprising molecular dynamics simulations and free energy calculations to computationally elucidate the molecular binding and specificity determinants of ?-wrapins binding to IAPP, and investigated additional ?-wrapins in complex with ?-syn. Subsequently, our studies will be used as a basis for the computationally design of novel ?-wrapin proteins with the highest recorded affinity and specificity sequestering one or most importantly all three amyloidogenic proteins. Both, the development of the novel transformative computational design tools that will be developed for the purpose of the current proposal, as well as the designed-engineered ?-wrapins that will be produced within the framework of the current proposal are expected to lead to great advancements both in the field of (i) computational design of novel proteins as well as (ii) health and innovative potential therapeutics. Experimental validation will be performed by Dr. Wolfgang Hoyer?s lab, one of the pioneers in discovering ?-wrapins as amyloid inhibitors. The experimentally validated engineered ?-wrapins may constitute molecules with applications in health. Potentially successfully designed ?-wrapins combining high affinity and multi-targeting properties for all amyloidogenic proteins of interest in the specific study may constitute an excellent and efficient direction for future advancements in Alzheimer?s and Parkinson?s diseases in place of existing molecules inhibiting aggregation of A? or ?-syn only.